Transition‐Metal‐Free Cross‐Dehydrogenative Coupling of Ethyl Arylacetates with Benzoic/Cinnamic Acids: A Practical Synthesis of α‐Acyloxy Esters

Abstract

An efficient cross-dehydrogenative coupling of benzylic C(sp 3 )ÀHo fe thyl arylacetates with benzoic/cinnamic acids has been developed to afford a-acyloxy esters in reasonablyh igh yields under environmentally benign conditions. Cross-dehydrogenative coupling (CDC) reactions have taken a central place in current day organic synthesis due to its advantages to construct carbon-carbon/carbon-heteroatomb onds. a-Acyloxy ketones and esters constitute the vital building block of aw ide range of natural products and pharmaceuticals. [1] a-Acyloxye sters can also be selectively hydrolyzed to the corresponding a-hydroxy esters having high product value in cosmetic, chemical, food, and pharmaceutical industries. [2,3] The installation of acyloxy substituent at benzylic positioni sa n enduring goal in organic synthesis, and many reports using benzylic/allylic C(sp 3 )ÀHa nd OÀHb onds involvingC DC protocol have appeareda dopting different strategies. [4][5][6] The selective oxidative cleavage of benzylic C(sp 3 )ÀHa nd CDC are especially important fort he formation of CÀOb onds, and have been accomplished using transition metal catalystss uch as Cu, Fe, Ru, Rh, Ir,a nd Pd in combination with different oxidants. [7] Jørgensen et al. have established ag eneralr oute for the rhodium-catalyzed NÀHa nd OÀHi nsertion of amides and carboxylic acids with a-diazo-b-ketoesters to afford a-amido and a-carboxylic-b-ketoesters, [8] whereas Feng group has recently illustrated an enantioselective insertiono fa-diazoestersa nd a-diazoketonesi nto OÀHb onds of carboxylic acids by using Rh 2 (OAc) 4 and achiral guanidine (Scheme 1). [9] Sharmaetal. extended the scope of reaction by using aR h 2 (esp) 2 -catalyzed OÀHi nsertion of 3-butynoic acid with diazo methylbenzoylacetate adoptingC onia-ene strategy. [10] The esterification of car-boxylic acids has also been achieved via continuous flow diazotization of amines, [11] iron-catalyzed intermolecular hydrothiolation of internal alkynes with thiosalicylic acids, [12] and by catalytic Mitsunobu reaction using recyclable azo reagents. [13] N-Heterocyclic carbene (NHC)-based reactions have also been identified to play an important role in constructing the benzoate ester via heteroacylationo fc arbonyl compounds. [14] A biocatalytic pathway involvingB aeyer-Villiger Monooxygenases (BVMO) has also been explored for the synthesis of enantiopure a-acylated hydroxy esters. [15] However,m ost of the aforementioned reactions are metal based and invariably make use of diazo esters in the presence of ar hodium catalyst. As an environmentally benign, inexpensivea nd practically useful methodology,t he advancement of transition-metal-free reactions is yet challenging. [16] Thus, new and eco-safep rotocols employing readily available startingm aterials are highly exigent to obtain a-acyloxy esters.In view of the above and as ap art of our continuedi nterest on metal-free synthesis, [17] we disclose herein ap ractical synthetic strategy adopting oxidative CDC of benzylic C(sp3)ÀHo f ethyl arylacetates w...

Iodine and DMSO as Surrogate of Hazardous Metal and Non‐Metal Reagents in Organic Synthesis

“…Specifically, rahodium metal has been used to catalyze the cross dehydrogenative coupling at the benzilic position, which involves Csp 3 −H oxidative cleavage for Carbon‐hetero atom bond formation (Scheme 54 (a–c)) [538–540] . Sharma and colleagues were able to achieve this reaction using catalytic amounts of iodine and an eco‐friendly base such as K 2 CO 3 (Scheme 54 (d)) [541] . The DMSO was chosen as the solvent, while ethyl arylacetates and benzoic acid were used as starting materials.…”

Recent progress in catalytic acyloxylation of C(sp3)‐H bonds

“…Singh with coworkers reported the acyloxylation of benzylic C(sp 3 )‐H groups of ethyl arylacetates of the type 191 with benzoic and cinnamic acids. [ 120 ] This metal‐free synthetic protocol utilized molecular iodine as oxidant and catalyst at the same time, and K 2 CO 3 as a base. A variety of ethyl arylacetates and carboxylic acids was used to afford a diverse range of products 192 with 42–78 % yields (Scheme 31).…”

Latest Advancements in Transition‐Metal‐Free Carbon‐Heteroatom Bond Formation Reactions via Cross‐ Dehydrogenative Coupling

“…Based on certain control experiments performed, the formation of α ‐iodo ester as an intermediate has been proposed. The possibility of radical pathway has been excluded since radical scavengers TEMPO/BHT did not affect the reaction [59] …”

“…A new CÀ O bond formation was achieved in presence of catalytic amount of molecular iodine and K 2 CO 3 in DMSO at 80 °C. [59] A series of α-acyloxy esters have been synthesized by coupling ethyl aryl acetates with benzoic/cinnamic acids under these conditions (Scheme 62). The reaction was optimized for various other solvents, catalysts and bases but none could afford the coupled product.…”

“…The possibility of radical pathway has been excluded since radical scavengers TEMPO/BHT did not affect the reaction. [59] Deb et al reported an intramolecular metal-free CÀ O bond formation reaction in 1,3-oxazines. This α-C sp3 À H oxygenation of tertiary amines in Betti base could be achieved using I 2 /TBHP system in DMF at 130 °C to afford the corresponding product in 93% yield (Scheme 63).…”